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The Future of Tumor Pathology
Path. Res. Pract. 179, 267-269 (1984)
Pathology in Europe
The Future of Tumor Pathology Invited paper. IXth European Congress of Pathology September 1983 Jan PontEm Institute of Pathology, University Hospital, Uppsala, Sweden
Examination of biopsies is the cornerstone of tumor pathology. Improved clinical imaging procedures and refinement of instrumentation have made scrutinization of small tissue specimens a major task of a practising tumor pathologist. The time is rapidly approaching when all tumor sites will be sampled prior to diagnosis and probably also during treatment. Microscopic analysis remains a surprisingly useful and accurate technique in answering two essential diagnostic questions a) is this lesion neoplastic and if so b) how can it be classified? Armed with this information, clinicians will be able to make a reasonably rational choice of treatment. Malignant cells are characterized by three properties: imperfectly controlled growth, improper social behaviour and capacity for infinite multiplication. Experimentally, any of these can be genetically impressed on cells without causing the severe structural aberrations which underlie 'atypia', and other empirically found correlates to malignant neoplasia. It is a lucky, but still poorly understood, circumstance that these morphologic traits can be assessed with such surprising accuracy. Atypia and other morphologic hallmarks of malignancy combine into very subtle patterns which skilled pathologists translate into classifications which by and large have remained stable over the years and also have become international standards. Research and clinical observations have clearly shown that cancers behave much more individually than suggested by current classification. Tumors of identical designation and clinical stage will develop differently with respect to prognosis, metastases, response to treatment etc. These individual traits can only be crudely assessed by morphology alone. In spite of the impressive success of morphologic methods there is clearly a need for extracting more information from tumor biopsies. Experimental research has revealed that, for instance, homing of metastases may relate to plasma membrane composition and that response to chemotherapy of leukemias depends on their precise stage of differentiation. © l!l84 by Gustav Fischer Verlag, Stuttgart
Many examples can be cited of the rapid advance of non-morphologic methods into diagnostic tumor pathology. DNA cytometry and the localization by monoclonal antibodies of practically all proteins of interest are probably only forerunners of powerful molecular techniques for the even more important elucidation of gene structure and function in cancer. The introduction of these and other modern techniques coupled to their great potential diagnostic value will present tumor pathology with an unprecedented challenge. For the first time serious alternatives to microscopy begin to emerge. Should future tumor diagnostic work based on biopsies be carried out in departments of pathology or should part of it be transferred to other disciplines? Most pathologists would emphatically maintain that biopsies are their "property" and that biochemists and immunologists are incapable of dealing with cancer diagnostic work in any serious or responsible manner. Unfortunately, pathologists do not in general seem ready to accept this challenge for a number of more or less rational reasons. 1. The work load on pathologists has increased to a point where too little time is left for introduction of new techniques. I believe there is a remedy for this - increased use of technical assistance and modern means of communication. Gross examination aided by photography could be assigned to specially trained technical assistants including dissection of lymph nodes etc. Screening of trivial specimens such as nevi etc. could probably also be carried out by technical assistants supervised by trained pathologists. More time for sophisticated analysis, less for routine tasks! Don't be afraid to train and supervise technicians to take their part of the diagnostic responsibilities. To employ new techniques always requires one to overcome the barriers of traditional inertia. Pathologists should realize that they can also fall into the trap of using a large routine workload as a pretence for avoiding change. 0344-0338/84/0179-0267$3.50/0
268 .
J. Ponten
2. The inherent attraction of morphology. There is an obvious satisfaction in grasping visible information and almost momentarily translate it directly into a clinically meaningful statement. The skill of a pathologist has quite appropriately been compared to that of an art critic, who immediately spots the qualities of a painting, its relation to other pieces of art and its contemporary significance. The joy and satisfaction of such a performance, which involves some of the highest associative capacities of the brain, are immense and will inevitably nurse a suspicious attitude of rivalling techniques. Could spectroscopy, computer-based pattern recognition and chemical paint analysis ever explain a van Gogh oil? Of course not, but it would certainly add something to the understanding of the objects depicted. The remedy here is for pathologists to be proud of their unsurpassed ability to extract meaning from structure but to accept that morphology can never give a complete picture of the performance of a cell and that "functional" tests can add valuable information which then often has to be extracted by tedious and complicated methodology. 3. The non-technical tradition of pathology. As a laboratory discipline pathology is still rather poorly developed. Few recent methods have been invented by pathologists. Major innovations such as electron microscopy are still not routine. Many pathologists do not master the preparation of stained slides and are even unfamiliar with the mechanics and optics of their favourite instrument - the microscope. The chemistry of fixation - an important routine in pathology - is still poorly understood. The reasons for this mysterious resistance to change are unknown. Part of it may be an unfortunate decision by other laboratory disciplines to secede from pathology, the traditional emphasis on autopsies, where all information is morphologic and a specialist training usually devoid of technical content. However, the roots may reach deeper than this. Pathology probably attracts people with a special ability of subjective pattern recognition and interpretation. Maybe that these 'humanistic' traits to some extent preclude genuine interest in development of new 'objective' techniques. 4. The lack of main-stream research in tumor pathology. Originally, pathology tried to resolve major problems as most glaringly demonstrated by the great Continental pathologists of the last century. Gradually, however, pathology has become more and more involved with less important scientific issues. This is a natural consequence of stringent adherence to morphologic techniques which in themselves are inadequate tools in experimental tumor biology. With rare exceptions, all major discoveries in the cancer field have been made outside of departments of clinical pathology. This has led to ignorance or even hostility in pathological circles with respect to experimental research. It is, on the other hand, also clear that laboratory
Lack of interest in main stream cancer research is probably the most serious problem and the most difficult to remedy. It calls for intellectual reorientation and acceptance of modern cell biology. This will be hard to implement not only because contemporary pathologists have little training outside of morphology but also because current curricula in pathology generally do not include an experimental activity. This is in contrast to many textbooks which contain excellent chapters on tumor biology. Ambitious top level cancer research and tough everyday diagnostic work within a single department may turn out to be the most fruitful interaction in the cancer field.
The future department of tumor pathology Laboratory results will become increasingly inportant in the management of cancer. Already pathology reports are decisive in determining therapy and their proper interpretation is therefore of paramount importance. Should different laboratory disciplines independently channel bits of information based on biopsy interpretation to the oncologists or should pathology continue to provide the decisive pieces of diagnostic information regardless of technique used? From many points of view, the latter alternative is preferable. Only if all types of data which can be obtained from biopsies are put into a joint perspective will the clinician get maximal benefit from tissue sampling. The ideal department of tumor pathology should be able to perform a technically unbiased extraction of the structural, immunological, genetic and biochemical information contained in tissue biopsies without duplication of unnecessary procedures. Clinicians should not have to resort to multiple biopsies only because they are analyzed in different laboratories. Since every alteration needs to be related to the malignant cells rather than benign stroma cells, all need microscopic verification. Altered proteins or genes have to be linked to cancer cells and not to any reactive elements - a condition which can only be met by in situ methods, i.e. the realm of pathologist. The ideal laboratory should be built on the principle that its objective is to furnish clinical oncology with as much information as possible from biopsies and to present the data from a synoptic standpoint to make their interpretation unambigous. Such an ambitious goal calls for certain major intellectual and organizational changes. Pathologists must learn not only to accept other methods but also to assess their practical validity. Competent groups have to be formed to introduce and use modern biochemistry, molecular biology, cytogenetics and immunology in tumor biopsy interpretation. These should profit also from participation of non-medically trained people. This rather complicated machinery needs to be integrated and revolve around three
experiments aimed at understanding human cancers often
axles! the dinico-pathologic value, development and
follow an unrealistic path because of lack of input from clinically experienced pathologists.
refinement of techniques and, indispensably, research in carcInogenesis.
The Future of Tumor Pathology . 269
Superficially, this would seem to require expansion beyond available resources. But this need not be the case. Instead it calls for friendly and cooperative merger of parts of pathology, biochemistry, immunology etc. into clinical
laboratory units which should be extremely valuable for one important future goal: vast improvements in diagnosis and treatment of cancer.
Received January 17, 1984· Accepted February 2, 1984
Key words: Tumor - Diagnosis - Future - Biopsy Prof.
J. Ponten, M. D., Institute of Pathology, Universiry Hospital, S-75185 Uppsala, Sweden
Pathology in Europe
The Future of Tumor Pathology Invited paper. IXth European Congress of Pathology September 1983 Jan PontEm Institute of Pathology, University Hospital, Uppsala, Sweden
Examination of biopsies is the cornerstone of tumor pathology. Improved clinical imaging procedures and refinement of instrumentation have made scrutinization of small tissue specimens a major task of a practising tumor pathologist. The time is rapidly approaching when all tumor sites will be sampled prior to diagnosis and probably also during treatment. Microscopic analysis remains a surprisingly useful and accurate technique in answering two essential diagnostic questions a) is this lesion neoplastic and if so b) how can it be classified? Armed with this information, clinicians will be able to make a reasonably rational choice of treatment. Malignant cells are characterized by three properties: imperfectly controlled growth, improper social behaviour and capacity for infinite multiplication. Experimentally, any of these can be genetically impressed on cells without causing the severe structural aberrations which underlie 'atypia', and other empirically found correlates to malignant neoplasia. It is a lucky, but still poorly understood, circumstance that these morphologic traits can be assessed with such surprising accuracy. Atypia and other morphologic hallmarks of malignancy combine into very subtle patterns which skilled pathologists translate into classifications which by and large have remained stable over the years and also have become international standards. Research and clinical observations have clearly shown that cancers behave much more individually than suggested by current classification. Tumors of identical designation and clinical stage will develop differently with respect to prognosis, metastases, response to treatment etc. These individual traits can only be crudely assessed by morphology alone. In spite of the impressive success of morphologic methods there is clearly a need for extracting more information from tumor biopsies. Experimental research has revealed that, for instance, homing of metastases may relate to plasma membrane composition and that response to chemotherapy of leukemias depends on their precise stage of differentiation. © l!l84 by Gustav Fischer Verlag, Stuttgart
Many examples can be cited of the rapid advance of non-morphologic methods into diagnostic tumor pathology. DNA cytometry and the localization by monoclonal antibodies of practically all proteins of interest are probably only forerunners of powerful molecular techniques for the even more important elucidation of gene structure and function in cancer. The introduction of these and other modern techniques coupled to their great potential diagnostic value will present tumor pathology with an unprecedented challenge. For the first time serious alternatives to microscopy begin to emerge. Should future tumor diagnostic work based on biopsies be carried out in departments of pathology or should part of it be transferred to other disciplines? Most pathologists would emphatically maintain that biopsies are their "property" and that biochemists and immunologists are incapable of dealing with cancer diagnostic work in any serious or responsible manner. Unfortunately, pathologists do not in general seem ready to accept this challenge for a number of more or less rational reasons. 1. The work load on pathologists has increased to a point where too little time is left for introduction of new techniques. I believe there is a remedy for this - increased use of technical assistance and modern means of communication. Gross examination aided by photography could be assigned to specially trained technical assistants including dissection of lymph nodes etc. Screening of trivial specimens such as nevi etc. could probably also be carried out by technical assistants supervised by trained pathologists. More time for sophisticated analysis, less for routine tasks! Don't be afraid to train and supervise technicians to take their part of the diagnostic responsibilities. To employ new techniques always requires one to overcome the barriers of traditional inertia. Pathologists should realize that they can also fall into the trap of using a large routine workload as a pretence for avoiding change. 0344-0338/84/0179-0267$3.50/0
268 .
J. Ponten
2. The inherent attraction of morphology. There is an obvious satisfaction in grasping visible information and almost momentarily translate it directly into a clinically meaningful statement. The skill of a pathologist has quite appropriately been compared to that of an art critic, who immediately spots the qualities of a painting, its relation to other pieces of art and its contemporary significance. The joy and satisfaction of such a performance, which involves some of the highest associative capacities of the brain, are immense and will inevitably nurse a suspicious attitude of rivalling techniques. Could spectroscopy, computer-based pattern recognition and chemical paint analysis ever explain a van Gogh oil? Of course not, but it would certainly add something to the understanding of the objects depicted. The remedy here is for pathologists to be proud of their unsurpassed ability to extract meaning from structure but to accept that morphology can never give a complete picture of the performance of a cell and that "functional" tests can add valuable information which then often has to be extracted by tedious and complicated methodology. 3. The non-technical tradition of pathology. As a laboratory discipline pathology is still rather poorly developed. Few recent methods have been invented by pathologists. Major innovations such as electron microscopy are still not routine. Many pathologists do not master the preparation of stained slides and are even unfamiliar with the mechanics and optics of their favourite instrument - the microscope. The chemistry of fixation - an important routine in pathology - is still poorly understood. The reasons for this mysterious resistance to change are unknown. Part of it may be an unfortunate decision by other laboratory disciplines to secede from pathology, the traditional emphasis on autopsies, where all information is morphologic and a specialist training usually devoid of technical content. However, the roots may reach deeper than this. Pathology probably attracts people with a special ability of subjective pattern recognition and interpretation. Maybe that these 'humanistic' traits to some extent preclude genuine interest in development of new 'objective' techniques. 4. The lack of main-stream research in tumor pathology. Originally, pathology tried to resolve major problems as most glaringly demonstrated by the great Continental pathologists of the last century. Gradually, however, pathology has become more and more involved with less important scientific issues. This is a natural consequence of stringent adherence to morphologic techniques which in themselves are inadequate tools in experimental tumor biology. With rare exceptions, all major discoveries in the cancer field have been made outside of departments of clinical pathology. This has led to ignorance or even hostility in pathological circles with respect to experimental research. It is, on the other hand, also clear that laboratory
Lack of interest in main stream cancer research is probably the most serious problem and the most difficult to remedy. It calls for intellectual reorientation and acceptance of modern cell biology. This will be hard to implement not only because contemporary pathologists have little training outside of morphology but also because current curricula in pathology generally do not include an experimental activity. This is in contrast to many textbooks which contain excellent chapters on tumor biology. Ambitious top level cancer research and tough everyday diagnostic work within a single department may turn out to be the most fruitful interaction in the cancer field.
The future department of tumor pathology Laboratory results will become increasingly inportant in the management of cancer. Already pathology reports are decisive in determining therapy and their proper interpretation is therefore of paramount importance. Should different laboratory disciplines independently channel bits of information based on biopsy interpretation to the oncologists or should pathology continue to provide the decisive pieces of diagnostic information regardless of technique used? From many points of view, the latter alternative is preferable. Only if all types of data which can be obtained from biopsies are put into a joint perspective will the clinician get maximal benefit from tissue sampling. The ideal department of tumor pathology should be able to perform a technically unbiased extraction of the structural, immunological, genetic and biochemical information contained in tissue biopsies without duplication of unnecessary procedures. Clinicians should not have to resort to multiple biopsies only because they are analyzed in different laboratories. Since every alteration needs to be related to the malignant cells rather than benign stroma cells, all need microscopic verification. Altered proteins or genes have to be linked to cancer cells and not to any reactive elements - a condition which can only be met by in situ methods, i.e. the realm of pathologist. The ideal laboratory should be built on the principle that its objective is to furnish clinical oncology with as much information as possible from biopsies and to present the data from a synoptic standpoint to make their interpretation unambigous. Such an ambitious goal calls for certain major intellectual and organizational changes. Pathologists must learn not only to accept other methods but also to assess their practical validity. Competent groups have to be formed to introduce and use modern biochemistry, molecular biology, cytogenetics and immunology in tumor biopsy interpretation. These should profit also from participation of non-medically trained people. This rather complicated machinery needs to be integrated and revolve around three
experiments aimed at understanding human cancers often
axles! the dinico-pathologic value, development and
follow an unrealistic path because of lack of input from clinically experienced pathologists.
refinement of techniques and, indispensably, research in carcInogenesis.
The Future of Tumor Pathology . 269
Superficially, this would seem to require expansion beyond available resources. But this need not be the case. Instead it calls for friendly and cooperative merger of parts of pathology, biochemistry, immunology etc. into clinical
laboratory units which should be extremely valuable for one important future goal: vast improvements in diagnosis and treatment of cancer.
Received January 17, 1984· Accepted February 2, 1984
Key words: Tumor - Diagnosis - Future - Biopsy Prof.
J. Ponten, M. D., Institute of Pathology, Universiry Hospital, S-75185 Uppsala, Sweden